Motor Cortex Lesions Research Articles

Coaction of individual and environmental factors: a review of intensive therapy paradigms for children with unilateral spastic cerebral palsy

Considerable variability exists in how children with unilateral spastic cerebral palsy respond to intensive upper extremity therapies. Individual and environmental factors interact to shape responsiveness.

Clinical outcomes from maximum-safe resection of primary and metastatic brain tumors using awake craniotomy

ObjectiveTo retrospectively analyze outcomes in patients undergoing awake craniotomies for tumor resection at our institution in terms of extent of resection, functional preservation and length of hospital stay. Patients and methodsAll cases of adults undergoing awake-craniotomy from September 2012–February 2015 were retrospectively reviewed based on an IRB approved protocol. Information regarding patient age, sex, cancer type, procedure type, location, hospital stay, extent of resection, and postoperative complications was extracted. Results76 patient charts were analyzed. Resected cancer types included metastasis to the brain (41%), glioblastoma (34%), WHO grade III anaplastic astrocytoma (18%), WHO grade II glioma (4%), WHO grade I glioma (1%), and meningioma (1%). Over a half of procedures were performed in the frontal lobes, followed by temporal, and occipital locations. The most common indication was for motor cortex and primary somatosensory area lesions followed by speech. Extent of resection was gross total for 59% patients, near-gross total for 34%, and subtotal for 7%. Average hospital stay for the cohort was 1.7days with 75% of patients staying at the hospital for only 24h or less post surgery. In the postoperative period, 67% of patients experienced improvement in neurological status, 21% of patients experienced no change, 7% experienced transient neurological deficits, which resolved within two months post op, 1% experienced transient speech deficit, and 3% experienced permanent weakness. ConclusionsIn a consecutive series of 76 patients undergoing maximum-safe resection for primary and metastatic brain tumors, awake-craniotomy was associated with a short hospital stay and low postoperative complications rate.

P034 Lesioned motor cortex neurophysiology in children with perinatal stroke

Introduction Perinatal stroke (PS) causes most hemiparetic cerebral palsy. Motor recovery is highly dependent on developmental plasticity in bilateral motor cortex. The fundamental neurophysiology of the lesioned motor cortex (M1) is poorly understood. Objective To characterize lesioned corticomotor neurophysiological properties in hemiparetic children with perinatal stroke. Methods Children 6–18 years with MRI-confirmed PS and hemiparesis were recruited (Alberta Perinatal Stroke Project). Transcranial magnetic stimulation (TMS) protocols applied to the lesioned M1 measured rest and active motor thresholds (RMT/AMT) and stimulus response curves (SRC:100-150RMT). Paired-pulse TMS explored short-latency intracortical inhibition and intracortical facilitation (SICI/ICF; 2/10 ms ISI). Measures were compared to the non-lesioned hemisphere and healthy controls (n = 40, median 12.2 years, range 8–18). Motor outcomes by blinded occupational therapists were Assisting Hand (AHA), Melbourne (MA) assessments and Box and Block (BB). Safety and tolerability were assessed. Results Of 45 children (median 11.3 years, 25 male; 65% arterial, 35% PVI), TMS of lesioned M1 evoked contralateral MEPs in only 12 (27%). No ipsilateral MEPs were recorded. Thresholds for evoking a stroke-side MEP were higher than the non-lesioned side (p = 0.04).The s-shaped SRC indicated that the morphology and responsiveness to increases in TMS intensities was preserved but shifted down compared to non-lesioned side or controls contralateral SRC. Contralateral SICI (−39.2%, −42.1%) and ICF (42.5%, 43.6%) effects were comparable between lesioned and non-lesioned sides (p = 0.43, p = 0.54, respectively), as well as controls SICI (p = 0.30) and ICF (p = 0.22). Latencies of MEPs from the lesion side (24.3 ms) were longer than contralateral, non-lesioned MEP (24.3 ms versus 21.6 ms, p = 0.003). The area under the SRC curve is correlated with all AHA (r = 0.9, p = 0.01), MEL (r = 0.9, p = 0.02) and BB (r = 0.8, p = 0.05). Protocols were well tolerated with no adverse events. Conclusion Cortical physiology of contralateral projections from the lesion side can be measured in hemiparetic children with PS using TMS. Individualized neurophysiology will further inform recently demonstrated therapeutic neuromodulation interventions in this population.

A Delay between Motor Cortex Lesions and Neuronal Transplantation Enhances Graft Integration and Improves Repair and Recovery.

We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged motor cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. Here, we report that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, and proliferation of grafted cells. More importantly, the delay dramatically increases the density of projections developed by grafted neurons and improves functional repair and recovery as assessed by intravital dynamic imaging and behavioral tests. These findings open new avenues in cell transplantation strategies as they indicate successful brain repair may occur following delayed transplantation.SIGNIFICANCE STATEMENT Cell transplantation represents a promising therapy for cortical trauma. We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. We demonstrate that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, proliferation, and the density of the projections developed by grafted neurons. More importantly, the delay has a beneficial impact on functional repair and recovery. These results impact the effectiveness of transplantation strategies in a wide range of traumatic injuries for which therapeutic intervention is not immediately feasible.

Use of the parallel beam task for skilled walking in a rat model of cerebral ischemia: A qualitative approach

The parallel beam task (PBT), in which animals walk across two elevated parallel beams, is commonly used to assess motor deficits in laboratory rodents. Performance of the PBT challenges postural balance, inter-limb coordination and skilled walking abilities, and is typically assessed by quantitative measures such as number of foot slips and/or successful traversals. We proposed that including qualitative movement analysis of skilled walking would increase resolution and sensitivity of PBT assessments in rats with cortical ischemic lesion. Pre-trained rats with a unilateral devascularization of the primary motor cortex and controls were recorded from lateral and ventral views as they traversed a PBT made of two parallel metal beams. The new qualitative skilled walking scoring system analyzed four elements of posture, limb placement, and targeting (limb rotation and position, number of placing attempts and foot slips) based on frame-by-frame video analysis. The analysis revealed that motor cortex lesions produced significant deficits in contralateral limb rotation and limb placement in both fore- and hind limbs, compared to ipsilateral limbs and control animals. Fore- and hind limbs showed different patterns in limb placement impairments. The results indicate that forelimb foot slips are a more sensitive measure of lesion-induced deficits than hind limb foot slips. Thus, the PTB is an effective task for the assessment of skilled walking and motor learning strategies especially when combined with qualitative movement analysis in rodent models of stroke.

Right Hemisphere Remapping of Naming Functions Depends on Lesion Size and Location in Poststroke Aphasia.

The study of language network plasticity following left hemisphere stroke is foundational to the understanding of aphasia recovery and neural plasticity in general. Damage in different language nodes may influence whether local plasticity is possible and whether right hemisphere recruitment is beneficial. However, the relationships of both lesion size and location to patterns of remapping are poorly understood. In the context of a picture naming fMRI task, we tested whether lesion size and location relate to activity in surviving left hemisphere language nodes, as well as homotopic activity in the right hemisphere during covert name retrieval and overt name production. We found that lesion size was positively associated with greater right hemisphere activity during both phases of naming, a pattern that has frequently been suggested but has not previously been clearly demonstrated. During overt naming, lesions in the inferior frontal gyrus led to deactivation of contralateral frontal areas, while lesions in motor cortex led to increased right motor cortex activity. Furthermore, increased right motor activity related to better naming performance only when left motor cortex was lesioned, suggesting compensatory takeover of speech or language function by the homotopic node. These findings demonstrate that reorganization of language function, and the degree to which reorganization facilitates aphasia recovery, is dependent on the size and site of the lesion.

Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model.

Multilineage-differentiating stress-enduring (muse) cells are endogenous nontumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+ cells from the bone marrow from cultured bone marrow-mesenchymal stem cells. After transplantation into neurological disease models, muse cells exert repair effects, but the exact mechanism remains inconclusive. We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human bone marrow-muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice. Approximately 28% of initially transplanted muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (≈62%), MAP2 (≈30%), and GST-pi (≈12%). Dextran tracing revealed connections between host neurons and muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side, and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human-specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.

Hindlimb spasticity after unilateral motor cortex lesion in rats is reduced by contralateral nerve root transfer.

Lower extremity spasticity is a common sequela among patients with acquired brain injury. The optimum treatment remains controversial. The aim of our study was to test the feasibility and effectiveness of contralateral nerve root transfer in reducing post stroke spasticity of the affected hindlimb muscles in rats. In our study, we for the first time created a novel animal hindlimb spastic hemiplegia model in rats with photothrombotic lesion of unilateral motor cortex and we established a novel surgical procedure in reducing motor cortex lesion-induced hindlimb spastic hemiplegia in rats. Thirty six rats were randomized into three groups. In group A, rats received sham operation. In group B, rats underwent unilateral hindlimb motor cortex lesion. In group C, rats underwent unilateral hindlimb cortex lesion followed by contralateral L4 ventral root transfer to L5 ventral root of the affected side. Footprint analysis, Hoffmann reflex (H-reflex), cholera toxin subunit B (CTB) retrograde tracing of gastrocnemius muscle (GM) motoneurons and immunofluorescent staining of vesicle glutamate transporter 1 (VGLUT1) on CTB-labelled motoneurons were used to assess spasticity of the affected hindlimb. Sixteen weeks postoperatively, toe spread and stride length recovered significantly in group C compared with group B (P<0.001). Hmax (H-wave maximum amplitude)/Mmax (M-wave maximum amplitude) ratio of gastrocnemius and plantaris muscles (PMs) significantly reduced in group C (P<0.01). Average VGLUT1 positive boutons per CTB-labelled motoneurons significantly reduced in group C (P<0.001). We demonstrated for the first time that contralateral L4 ventral root transfer to L5 ventral root of the affected side was effective in relieving unilateral motor cortex lesion-induced hindlimb spasticity in rats. Our data indicated that this could be an alternative treatment for unilateral lower extremity spasticity after brain injury. Therefore, contralateral neurotization may exert a potential therapeutic candidate to improve the function of lower extremity in patients with spastic hemiplegia.

Physiological and behavioral effects of β-tACS on brain self-regulation in chronic stroke.

Unlike in healthy controls, sensorimotor β-desynchronization (β-ERD) is compromised in stroke patients, i.e., the more severe the patient's motor impairment, the less β-ERD. This, in turn, provides a target substrate for therapeutic brain self-regulation and neurofeedback. Transcranial alternating current stimulation (tACS) has been shown to modulate brain oscillations during and after stimulation, and may thus facilitate brain self-regulation during neurofeedback interventions. Twenty severely impaired, chronic stroke patients performed kinesthetic motor-imagery while a brain-robot interface transformed β-ERD (17-23Hz) of the ipsilesional sensorimotor cortex into opening of the paralyzed hand by a robotic orthosis. In a parallel group design, β-tACS (20Hz, 1.1mA peak-to-peak amplitude) was applied to the lesioned motor cortex either continuously (c-tACS) before or intermittently (i-tACS) during the intervention. Physiological effects of β-tACS were studied using electroencephalography. The patients' ability for brain self-regulation was captured by neurofeedback performance metrics. i-tACS - but not c-tACS - improved the classification accuracy of the neurofeedback intervention in comparison to baseline. This effect was mediated via the increased specificity of the classification, i.e., reduced variance of resting oscillations. Neither i-tACS nor c-tACS had aftereffects following the stimulation period. β-tACS may constitute an adjunct neuromodulation technique during neurofeedback-based interventions for stroke rehabilitation.

Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy

AimTo determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more‐affected motor cortex in children with unilateral spastic cerebral palsy (CP).MethodTwenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I–III). We used DTI tractography to reconstruct the CST projecting from the more‐affected motor cortex. We mapped the motor representation of the more‐affected hand by stimulating the more‐ and the less‐affected motor cortex measured with single‐pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI.Results DTI tractography successfully identified the CST controlling the more‐affected hand (sensitivity=82%, specificity=78%).InterpretationContralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI‐identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures.

Retraction: The role of compensatory movements patterns in spontaneous recovery after stroke.

[This retracts the article on p. 2671 in vol. 27.].

Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model.

Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 kDa, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson's disease.

Commentary on "Facilitation of the Lesioned Motor Cortex During Tonic Contraction of the Unaffected Limb Corresponds to Motor Status After Stroke".

Commentary on "Facilitation of the Lesioned Motor Cortex During Tonic Contraction of the Unaffected Limb Corresponds to Motor Status After Stroke".

Facilitation of the Lesioned Motor Cortex During Tonic Contraction of the Unaffected Limb Corresponds to Motor Status After Stroke.

Contraction of the muscles of the unaffected hand is associated with enhanced activation of lesioned motor cortex (ie, crossed facilitation) in some individuals after stroke. However, the association between crossed facilitation and motor function status remains unclear. We investigated whether existence of crossed facilitation corresponds to motor status of the affected upper limb after stroke. Data were collected from 58 participants with unilateral stroke. The Fugl-Meyer assessment of upper extremity (FMA-UE) was used to evaluate motor status. Motor-evoked potentials (MEPs) were elicited from the abductor pollicis brevis (ABP) of the affected side under 3 conditions: rest, tonic contraction of the ABP of the unaffected side, or tonic contraction of the tibialis anterior of the unaffected side. In 28 of the 58 participants, MEPs could be elicited from the affected ABP at rest; these participants also exhibited crossed facilitation during contraction on the unaffected side. Participants with MEPs at rest exhibited higher FMA-UE scores (53.04 ± 2.59) compared with participants with absent MEP (19.83 ± 1.60; Z = -6.21). Seven participants with no MEPs at rest had MEPs with crossed facilitation; their FMA-UE scores were higher compared with the 23 who had no ABP MEP under any condition (Z = -2.66). FMA-UE scores were positively correlated with the amount of crossed facilitation during the APB task (r = 0.68) and the tibialis anterior task (r = 0.54). In some participants, MEPs in the affected hand muscle were enhanced by tonic contraction of the muscles on the unaffected side even if no MEP could be evoked at rest. The degree of crossed facilitation in the affected hand muscle was correlated with the level of motor function of the affected upper limb, and the FMA-UE score could classify the presence/absence of crossed facilitation.Video abstract available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A117).

Editorial: Principles Underlying Post-Stroke Recovery of Upper Extremity Sensorimotor Function – A Neuroimaging Perspective

Editorial: Principles Underlying Post-Stroke Recovery of Upper Extremity Sensorimotor Function – A Neuroimaging Perspective

A Within-Animal Comparison of Skilled Forelimb Assessments in Rats.

A variety of skilled reaching tasks have been developed to evaluate forelimb function in rodent models. The single pellet skilled reaching task and pasta matrix task have provided valuable insight into recovery of forelimb function in models of neurological injury and disease. Recently, several automated measures have been developed to reduce the cost and time burden of forelimb assessment in rodents. Here, we provide a within-subject comparison of three common forelimb assessments to allow direct evaluation of sensitivity and efficiency across tasks. Rats were trained to perform the single pellet skilled reaching task, the pasta matrix task, and the isometric pull task. Once proficient on all three tasks, rats received an ischemic lesion of motor cortex and striatum to impair use of the trained limb. On the second week post-lesion, all three tasks measured a significant deficit in forelimb function. Performance was well-correlated across tasks. By the sixth week post-lesion, only the isometric pull task measured a significant deficit in forelimb function, suggesting that this task is more sensitive to chronic impairments. The number of training days required to reach asymptotic performance was longer for the isometric pull task, but the total experimenter time required to collect and analyze data was substantially lower. These findings suggest that the isometric pull task represents an efficient, sensitive measure of forelimb function to facilitate preclinical evaluation in models of neurological injury and disease.

A Small Motor Cortex Lesion Abolished Ocular Dominance Plasticity in the Adult Mouse Primary Visual Cortex and Impaired Experience-Dependent Visual Improvements.

It was previously shown that a small lesion in the primary somatosensory cortex (S1) prevented both cortical plasticity and sensory learning in the adult mouse visual system: While 3-month-old control mice continued to show ocular dominance (OD) plasticity in their primary visual cortex (V1) after monocular deprivation (MD), age-matched mice with a small photothrombotically induced (PT) stroke lesion in S1, positioned at least 1 mm anterior to the anterior border of V1, no longer expressed OD-plasticity. In addition, in the S1-lesioned mice, neither the experience-dependent increase of the spatial frequency threshold (“visual acuity”) nor of the contrast threshold (“contrast sensitivity”) of the optomotor reflex through the open eye was present. To assess whether these plasticity impairments can also occur if a lesion is placed more distant from V1, we tested the effect of a PT-lesion in the secondary motor cortex (M2). We observed that mice with a small M2-lesion restricted to the superficial cortical layers no longer expressed an OD-shift towards the open eye after 7 days of MD in V1 of the lesioned hemisphere. Consistent with previous findings about the consequences of an S1-lesion, OD-plasticity in V1 of the nonlesioned hemisphere of the M2-lesioned mice was still present. In addition, the experience-dependent improvements of both visual acuity and contrast sensitivity of the open eye were severely reduced. In contrast, sham-lesioned mice displayed both an OD-shift and improvements of visual capabilities of their open eye. To summarize, our data indicate that even a very small lesion restricted to the superficial cortical layers and more than 3mm anterior to the anterior border of V1 compromised V1-plasticity and impaired learning-induced visual improvements in adult mice. Thus both plasticity phenomena cannot only depend on modality-specific and local nerve cell networks but are clearly influenced by long-range interactions even from distant brain regions.

Motor Learning Consolidates Arc-Expressing Neuronal Ensembles in Secondary Motor Cortex

Motor behaviors recruit task-specific neuronal ensembles in motor cortices, which are consolidated over subsequent learning. However, little is known about the molecules that can identify the participating neurons and predict the outcomes of the consolidation process. Using a mouse rotarod-learning task, we showed that lesion or inactivation of the secondary motor (M2) cortex disrupts learning of skilled movements. We tracked the endogenous promoter activity of the neuronal activity-regulated gene Arc in individual M2 neurons during rotarod learning by in vivo two-photon imaging of a knockin reporter. We found that task training initially recruits Arc-promoter-activated neurons and then consolidates them into a specific ensemble exhibiting persistent reactivation of Arc-promoter. The intensity of a neuron's initial Arc-promoter activation predicts its reactivation probability and neurons with weak initial Arc-promoter activation are dismissed from the ensemble during subsequent training. Our findings demonstrate a task-specific Arc-dependent cellular consolidation process in M2 cortex during motor learning.

Action: The Role of Motor Cortex Challenged

The motor cortex is often considered the main controller for movement, but a new study shows that well-trained paw movements can be performed with equal precision after lesions of the entire motor cortex; the motor cortex is, however, required for learning a new task in naïve animals.

The Effect of Lesion Size on the Organization of the Ipsilesional and Contralesional Motor Cortex

Recovery of hand function following lesions in the primary motor cortex (M1) is associated with a reorganization of premotor areas in the ipsilesional hemisphere, and this reorganization depends on the size of the lesion. It is not clear how lesion size affects motor representations in the contralesional hemisphere and how the effects in the 2 hemispheres compare. Our goal was to study how lesion size affects motor representations in the ipsilesional and contralesional hemispheres. In rats, we induced lesions of different sizes in the caudal forelimb area (CFA), the equivalent of M1. The effective lesion volume in each animal was quantified histologically. Behavioral recovery was evaluated with the Montoya Staircase task for 28 days after the lesion. Then, the organization of the CFA and the rostral forelimb area (RFA)—the putative premotor area in rats—in the 2 cerebral hemispheres was studied with intracortical microstimulation mapping techniques. The distal forelimb representation in the RFA of both the ipsilesional and contralesional hemispheres was positively correlated with the size of the lesion. In contrast, lesion size had no effect on the contralesional CFA, and there was no relationship between movement representations in the 2 hemispheres. Finally, only the contralesional RFA was negatively correlated with chronic motor deficits of the paretic forelimb. Our data show that lesion size has comparable effects on motor representations in premotor areas of both hemispheres and suggest that the contralesional premotor cortex may play a greater role in the recovery of the paretic forelimb following large lesions.